Denosumab and bisphosphonates: rivals or potential "partners"? A "hybrid" molecule hypothesis

Bisphosphonates are well established as the treatment of choice for disorders of excessive bone resorption, including osteoporosis. They bind bone mineral with high affinity and through internalization by the resorbing osteoclasts, affect their function and survival. Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine essential for osteoclast differentiation, activation, and survival. Denosumab, a human monoclonal antibody that neutralizes RANKL, constitutes a promising antiresorptive agent for osteoporosis treatment. However, its presumable interaction with the immune system could adversely affect immune response resulting in increased risk of infections. We hypothesize that bisphosphonates could serve as a vehicle for the delivery of denosumab selectively to the skeleton. Thus, the effect on the immune system could be minimized, along with a potential increase in the antiresorptive efficacy, as a result of the combined action of denosumab and the bisphosphonate on the earlier and later stages of osteoclast life, respectively.     

Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial

BACKGROUND: Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. METHODS: 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. FINDINGS: Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI -0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4.4, 95% CI 1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. INTERPRETATION: Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.     

A study on the association with hepatitis B and hepatitis C in 1557 patients with lichen planus

Background Previous reports have demonstrated contradicting results on the association between lichen planus and hepatitis. Objectives The aim of this study was to investigate the association between lichen planus and viral hepatitis. Methods Patients with lichen planus were compared with controls regarding the prevalence of viral hepatitis in a case‐control study using logistic multivariate regression models. The study was performed utilizing the medical database of Clalit Health Services. Results The study included 1557 lichen planus patients over the age of 20 years and 3115 age‐ and gender‐matched controls. The prevalence of hepatitis C in patients with lichen planus was higher than that in the control group (1.9%, 0.4% respectively, P < 0.001). In a multivariate analysis, lichen planus was associated with hepatitis C (OR 4.19, 95% CI 2.21; 7.93). The prevalence of hepatitis B in patients with lichen planus was similar to that in the control group (0.9%, 0.5% respectively, P = 0.12). A multivariate analysis revealed that lichen planus was not associated with hepatitis B (OR 1.69, 95% CI 0.82; 3.47). Conclusion Lichen planus is associated with hepatitis C but not with hepatitis B. Physicians who care for patients with lichen planus should consider screening patients with lichen planus for hepatitis C.     

Progression of Rebound-Associated Vertebral Fractures Following Denosumab Discontinuation Despite Reinstitution of Treatment: Suppressing Increased Bone Turnover May Not Be Enough

Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.     

Two year cumulative incidence of trunk abnormalities in a schoolpopulation in Rotterdam, The Netherlands

We conducted a study of the 2 year cumulative incidence of trunkabnormalities in a cohort of 3,071 11 year old children (1,621boys, 1,450 girls). The following data were recorded: height,weight, signs of puberty and menarche. Trunk abnormality wasassessed in the erect child (asymmetry of shoulders and waistline,imbalance of the trunk, scoliosis, lordosis, kyphosis, swaybackand flexibility) and by the forward bending test (FBT) (ribhump or lumbar prominence, persisting scoliosis, kyphosis anddeviant lateral aspect). A normal FBT both at baseline and atfollow-up was found in 84% of the boys and in 79% of the girls.The 2 year cumulative incidence of an abnormal FBT was 10% inboys and 13% in girls.     

Complicated migraine and migraine variants.

Curr Pain Headache Rep. 2002;6:233-239.
This article reviews the less frequently encountered varieties of migraine. It is suggested that these disorders be approached by evaluating possible underlying etiologies before positively diagnosing migraine. This decreases the likelihood of "missing" structural or metabolic disorders. The classification, diagnostic evaluation, differential diagnosis, and treatment options of these disorders is reviewed and a selection of references appended for additional information.
Comment: Dr. Rothner is one of the most prominent pediatric neurology headache specialists in the country, and he sees a variety of atypical presentations of migraine. This is an excellent review of such presentations. SJT     

The effect of the Fanconi anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation

Fanconi anemia (FA) is an autosomal recessive disease marked by developmental defects, bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA cross-linking and alkylating agents and accumulate in the G2 phase of the cell cycle in response to these agents. FA cells also display genomic instability, suggesting a possible defect in the p53 pathway. To test the effect of heterologous expression of FAC cDNA on drug-induced cytotoxicity, G2 accumulation, and p53 induction in FA cells, we compared two isogenic FA cell lines: HSC536N (mock), a FA type C cell line sensitive to mitomycin C (MMC), and the same cell line transfected (corrected) with wild-type FAC cDNA (HSC536N [+FAC]). HSC536N (+FAC) cells showed a 30-fold increase in resistance to MMC concentration. Similarly, increases in resistance were observed following exposure to cisplatin, carboplatin, and cyclophosphamide. In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment. To analyze the possible interaction of FAC with the p53 pathway, we analyzed p53 induction in mock and corrected cell lines following exposure to MMC. HSC536N (mock) cells induced p53 at lower MMC concentrations than HSC536N (corrected). Caffeine, a known G2 checkpoint inhibitor, not only inhibited G2 accumulation seen in both cell lines but also caused the resistant HSC536N (+FAC) to become as sensitive to MMC as HSC536N (mock) cell line. We conclude that the FAC protein has a specific cytoprotective effect and may function as a cell cycle regulator of the G2 phase of the cell cycle.